Convection-enhanced delivery (CED) describes a method of direct drug delivery to the brain though intraparenchymal microcatheters along an infusion-mediated pressure gradient. The technique allows drugs which do not cross the blood-brain barrier to be delivered in therapeutic concentrations throughout large volumes of brain tissue, whilst minimizing systemic exposure.
Since Bobo et al.'s original description of pressure-mediated infusion of macromolecules in white matter (Bobo et al., 1994), CED of therapeutic agents has been applied to a wide range of neurological disorders in both experimental studies and clinical trials. The majority of clinical studies have focused on disorders in which the pathology is localised to either white matter, or to deep gray matter structures such as malignant glioma and Parkinson's Disease. Direct delivery of therapeutics to the cerebral cortex, however, remains challenging.
Targeting therapeutic agents to the cerebral cortex could be beneficial in a number of neurological diseases, most notably Alzheimer's disease and other forms of dementia, amyotrophic lateral sclerosis, multiple sclerosis and stroke. Convection-enhanced delivery of adeno-associated virus (AAV)-based vectors to the thalamus has previously been shown to result in transgene expression in widespread cortical areas as a consequence of both anterograde and retrograde axonal transport of AAV vectors. However, selective targeting of agents to limited areas of cortex would require convection-enhanced delivery to specific thalamic nuclei which are not easily identified with conventional imaging methods. Additionally, due to the location of the thalamus deep within the brain surgical targeting to this area can be difficult and associated with increased risks of complications such as haemorrhage.
Intrathecal delivery of therapeutic agents is known for spinal anaesthesia, chemotherapy and pain management. However, this delivery route is associated with a large number of side effects such as nausea and dizziness and is therefore not suitable for more widespread application.
It is an object of the present invention to provide a new delivery route for therapeutic agents into the central nervous system (CNS), particularly into the cerebral cortex and spinal cord.